Tachykinin is a general term for a group of peptides having similar structures. In mammals, Substance P (SP), neurokinin A (NKA) and neurokinin B (NKB) are representative tachykinins. These tachykinins are neuro-peptides which are widely distributed in a living body. Among them, Substance P has been most fully investigated for physiological functions. Substance P is a peptide consisting of 11 amino acids and exhibits hypotensive action, smooth muscle constricting action, sialagogue action, neuron exciting action, pain inducing action, etc. Substance P has been known to be concerned with various diseases such as those of the digestive system, nervous system and respiratory system. It has also been suggested to be deeply associated especially with inflammation, allergy, carcinoid syndrome, chronic pain, headache, Crohn disease, depression and vomiting. Accordingly, an antagonist for a tachykinin such as Substance P is applicable and useful as an anti-inflammatory agent, anti-allergic agent, analgesic, antiemetic, agent for irritable colon syndrome, agent for dermal disease, agent for vasospastic disease, agent for cerebral ischemic disease, antidepressant, antianxiety agent, agent for autoimmune disease, a muscle relaxant or an antispasmodic.
Various tachykinin antagonists have been developed and reported with an object of development of therapeutic agents for the above-mentioned diseases in which tachykinins participate (cf. Japanese Laid-Open Patent Publications Hei-06/509332, Hei-06/509087, Hei-06/509090, Bioorg. Med. Chem. Lett., 4, 16, 1903-1908 (1994), J. Med. Chem., 41, 4623-4635 (1998), J. Med. Chem., 43, 4416-4427 (2000) etc.). However, tachykinin antagonists which have heretofore been found have problems of performance in vivo such as undesirable transfer into blood and adverse effects, and none of them have been put into the market with approval as a pharmaceutical agent.
The present inventors have carried out intensive investigations for piperazine derivatives and have found novel 2-phenylpiperazine derivatives which have a good tachykinin antagonistic action and are useful as pharmaceutical agents, whereupon the present invention has been accomplished.
The present invention solves the above-mentioned problems and provides useful, novel compounds as tachykinin antagonists having high safety and a preferred behavior in vivo.